Abstract Viruses rarely enter the brain but when they do, the effects can be devastating. An example is Herpes Simplex encephalitis (HSE), a rare disease in adults usually caused by Herpes Simplex virus type 1 (HSV-1) occurring most commonly in persons already latently infected with the virus. Although some cases of HSE occur in persons with genetic problems of the immune system or are heavily immunosuppressed, most affected persons have no overt problem with their immune systems. An explanation why HSE occurs in such persons is still needed. We hypothesize that HSE occurs during a coalescence of events, which included viral reactivation from latency at a time when one or more components of the immune system is being compromised, perhaps temporarily, by a change in some metabolic function. These ideas cannot be tested in humans but we have established a mouse model in which events leading up to HSE can be evaluated. Thus we could show in a mouse model that inhibition of glucose metabolism with the molecule 2-deoxyglucosue from the time of local infection with HSV-1 resulted in the majority of animals developing HSE. We plan to verify and extend these preliminary findings and search for a mechanistic explanation for the outcome. We anticipate that the 2DG therapy could impair some stages of immune defense, which normally protect against infection of the central nervous system. The first is proposed to be a blunting of the function of one or more innate immune components at the infection site, or within the local nerve ganglion. This prevents innate cells from functioning sufficiently to limit the extent of local viral replication and also minimizes productive infection of neurons in the local ganglion. The second component is proposed to be an effect on the expansion or effector function of CD8 T cells which in normal circumstances protect neurons and prevents virus upon reactivation from latency from spreading to the brain. The proposal is designed to test our guiding hypotheses. We anticipate that our findings could result in changes in diagnostic procedures and therapeutic management of HSE. Thus, in addition to the currently used antiviral drug treatment any detected metabolic abnormalities could be corrected as well, with the combination therapy strategy minimizing the consequences of the HSE syndrome.